Tobacco is one of the most widely abused substances, killing more than 438,000 US citizens each year. Economically, smoking is responsible for about 7% of total US health care costs, or an estimated $167 billion each year. Genetic and epidemiological studies demonstrate that nicotine dependence (ND) is a complex disorder determined by genetic and environmental factors. Our previous meta-analysis of reported twin studies indicated that the weighted mean heritability for ND is 56% in adult smokers. To identify susceptibility loci for ND, we performed four genome-wide linkage studies on three independent samples, in which the African American (AA) and European American (EA) samples of the Mid-South Tobacco Family (MSTF) cohort were recruited by us during the first funding period of this grant. Our linkage analyses revealed four regions on chromosomes 9 (two regions), 11, and 18, in both the AA and EA samples of the MSTF cohort. In addition, we identified five regions on chromosomes 2, 4, 10, 12, and 17, which are specific for the EA sample, and two more regions, on chromosomes 10 and 13, that are unique to the AA sample. Considering that 1) we first reported significant linkage on chromosome 10 and suggestive linkage on chromosomes 9, 11, and 13 for ND in the AA population and 2) we have the largest collection of samples from this ethnic group in the US, in the current application, we seek support to follow up and expand our ongoing efforts in searching susceptibility genes for ND. Specifically, our aims are: 1) To perform high density association study on our AA family sample to screen for both common and rare risk variants for ND; 2) To have sufficient power to detect the small effect of susceptibility loci for ND, we plan to continue our recruitment effort, with the final goal of collecting 2,000 unrelated individuals with ND and 2,000 unrelated control individuals who have tried tobacco smoking but did not develop ND symptoms; and 3) To replicate nominal significantly associated single nucleotide polymorphisms (SNPs) identified in the AA family sample from Aim 1 using 2,000 AA cases and 2,000 AA controls recruited from Aim 2. We expect that such a sample size will have sufficient power to detect 80% of true effects with an odds ratio (OR) as low as 1.3. We expect the completion of the proposed studies to greatly advance our understanding of the genetic determinants of ND in African American smokers that eventually will allow targeting of novel prevention and treatment strategies to individuals at risk.